In the central nervous system neurons expressing prepro-orexin, the precursor from which orexin is produced, are found in the perifornical nucleus, the dorsal hypothalamus and the lateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23): 9996-10015). Orexinergic cells in these nuclei project to many areas of the brain, extending rostrally to the olfactory bulbs and caudally to the spinal chord (A. N. van den Pol, J. Neurosci., 1999, 19(8): 3171-3182). The orexins bind to two high affinity receptors, termed Orexin-1 and Orexin-2 receptors. The orexin-1 receptor is selective in favor of orexin A, while the orexin-2 receptor binds both orexins with similar affinities. The broad CNS distribution of orexin projections and neurons expressing orexin receptors is suggestive of orexin involvement in a number of physiological functions such as feeding, drinking, arousal, stress, metabolism and reproduction. A recent paper describing targeted necrosis of cells expressing prepro-orexin suggests the most physiologically important roles of the orexins are likely to be effects on arousal, feeding and metabolism (J. Hara et al., Neuron, 2001, 30:345-354). A prominent orexin neuronal projection via the vagus nerve probably mediates published central orexin effects on cardiac parameters (W. K. Samson et al., Brain Res., 1999, 831:248-253; T. Shirasaka et al., Am. J. Physiol., 1999, 277:R1780-R1785; C.-T. Chen et al., Am. J. Physiol., 2000, 278:R692-R697), gastric acid secretion and gastric motility (A. L. Kirchgessner and M.-T. Liu, Neuron, 1999, 24:941-951; N. Takahashi et al., Biochem. Biophys. Res. Commun., 1999, 254:623-627).
A number of factors suggest the orexin system is an important modulator of arousal. Orexin given i.c.v. increases the time rodents spend awake (D. C. Piper et al., Eur. J. Neurosci., 2000, 12:726-730) as measured using EEG and EMG recordings. Orexin-mediated effects on arousal are linked to orexin neuronal projections to histaminergic neurons in the tuberomammillary nucleus and can be blocked with an H1 antihistamine (A. Yamanaka et al., Biochem. Biophys. Res. Commun., 2002, 290:1237-1245). TMN histaminergic neurons express orexin-2 receptor and less orexin-1 receptor. Rodents whose pre-pro orexin gene has been knocked out (R. M. Chemelli et al., Cell, 1999, 98:437-451) or whose orexigenic neurons have been killed (J. Hara et al.) display altered sleep/wake cycles similar to narcolepsy. The dog models of narcolepsy have been shown to have a mutant and non-functional orexin-2 receptor (L. Lin et al., Cell, 1999, 98:365-376). Human narcolepsy appears to be linked to deficient orexin signaling, most likely related to immune ablation of orexinergic neurons in the lateral hypothalamus (E. Mignot et al., Am. J. Hum. Genet., 2001, 68:686-699; E. Mignot and E. Thorsby, N. Engl. J. Med., 2001, 344(9):692). In rare cases human narcoleptics have also been identified with mutant orexin-2 receptors (C. Peyron et al., Nat. Med., 2000, 6(9):991-997).
Disorders of the sleep-wake cycle are therefore likely targets for orexin-2 receptor antagonist therapy. Examples of such disorders include sleep-wake transition disorders, insomnia, restless legs syndrome, jet-lag and sleep disorders secondary to neurological disorders (manias, depressions, manic depression, schizophrenia, pain syndromes and the like).
The orexin system also interacts with brain dopamine systems. Intracerebroventricular injections of orexin increase locomotor activity, grooming and stereotypy; these behavioral effects are reversed by administration of D2 dopamine receptor antagonists (T. Nakamura et al., Brain Res., 2000, 873:181-187). Orexin-2 antagonists may therefore be useful to treat neurological disorders such as Parkinson's Disease, Gilles de la Tourette's Syndrome, anxiety, delirium and dementias.
Effects of the orexins on body weight are likely to be mediated by orexin-mediated increases in appetite (T. Sakurai et al., Cell, 1998, 92:573-585) and alterations in metabolism (M. Lubkin and A. Stricker-Krongrad, Biochem. Biophys. Res. Commun., 1998, 253:241-245). Some orexin effects on appetite and metabolism may be mediated in the gut, where orexins alter gastric acid secretion and gastric motility. Orexin antagonists are therefore likely therapies for obesity and may, through weight loss, be useful to treat consequences of obesity such as insulin resistance/type 2 diabetes, hyperlipidemia, gallstones, angina, high blood pressure, breathlessness, infertility, sleep apnea, back pain, joint pain, varicose veins and osteoarthritis. Conversely, the orexin system appears to be involved in anorectic/bulemic/exercise related amenorrhea and could therefore be useful in fertility control.
Orexins and their receptors have been found in both the myenteric and submucosal plexus of the enteric nervous system (A. L. Kirchgessner and M.-T. Liu). The orexins have been shown to increase motility in vitro (A. L. Kirchgessner and M.-T. Liu) and to stimulate gastric acid secretion in vivo (N. Takahashi et al.). Orexin effects on the gut may be driven by a projection via the vagus nerve (A. N. van den Pol), as vagotomy or atropine prevent the effect of a central (i.c.v) injection of orexin on gastric acid secretion (N. Takahashi et al.). Orexin antagonists are therefore potential treatments for ulcers, irritable bowel syndrome, diarrhea and gastroesophageal reflux.
Intracerebroventricularly administered orexins have been shown to increase mean arterial pressure and heart rate in freely moving (awake) animals (W. K. Samson et al.; T. Shirasaka et al.) and in urethane anaesthetized animals (C.-T. Chen et al.), with similar results. Orexin antagonists are therefore candidates for treatment of hypertension, angina pectoris, arrhythmias and acute heart failure.